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Chapter 9 : Antibiotic Resistance by Efflux Pumps
Active efflux can be clinically relevant for β-lactam antibiotics, macrolides, the pristinamycin peptides, fluoroquinolones, and most classically the tetracyclines. From bioinformatic analysis four protein families of efflux pumps that can function in antibiotic resistance have been described. The pumps driven by proton motive force (ΔpH) are categorized in the major facilitator subfamily (MFS), the small multidrug regulator (SMR) family, or the RND (resistance/nodulation/ cell division) family, based on projected size and the need for partner proteins and subunits. A significant breakthrough in understanding the architecture of an ABC type transporter has been obtained by crystallization of the MsbA protein from Escherichia coli, at a relatively low resolution, but sufficient to reveal orientation of nucleotide binding domains (NBDs) to transmembrane domains (TMDs) and allowing a model for transporter action. MsbA is homologous to human MDR-1 and mouse MDR3, multidrug resistance transporters that are thought to act physiologically as lipid and phospholipid ‘‘flippases,’’ moving phospholipid molecules from the inner to the outer layer of the membrane bilayer. E. coli O157:H7 exhibits resistance to streptomycin, tetracycline, and sulfa drugs and may do so through reduction of outer membrane permeability for uptake.